Background. The proposed research addresses the important concept that inflammation and immunity play an important role in hypertension. Two recent observations provide the background for our proposal. One is the flnding that the vagus exerts an anti-inflammatory influence on the immune system by activating a-7 nicotinic cholinergic receptors. The other is the essential contribution of the adaptive immune system and T lymphocytes to chronic angiotensin II dependent hypertension. Our focus is on the role ofthe innate immune system in a genetic model of hypertension, the spontaneously hypertensive rat (SHR). Our early results recentiy published in Circulation Research indicate that nicotine exerts an anti-inflammatory influence on splenocytes of Wistar Kyoto (WKY) rats in contrast to a marked proinflammatory response seen in spleno- cytes of SHR prior to the onset of hypertension. Hypothesis. The innate immune system in genetic hypertension is abnormally regulated by the autonomic nervous system to trigger proinflammatory responses to endogenous antigens. These induce pathologic renal and vascular changes that initiate and sustain the hypertensive state. Experimental Plan. The intracellular toll-like receptors (TLR) 7/8 and 9 will be activated with speciflc ligands to induce cytokine release and upregulate proinflammatory genes in isolated splenocytes and in vivo. Re- sponses will be obtained prenatally and at various ages in WKY and in SHR as hypertension develops and progresses. Regulation of TLR-induced inflammatory responses by activation of nicotinic cholinergic or Ang II ATI receptors will conflrm the importance of neurohormonal receptors on the innate immune system and hence on the hypertensive state. The phenotypic expression of hypertension and end-organ renal and vas- cular damage will be correlated with the gene and protein expressions in those tissues and their inflltration with immune cells. We will attempt to induce hypertension in WKY by prolonged activation of TLRs and in Fl hybrids (SHR-WKY) by adoptive transfer of splenocytes and bone marrow from SHR. The importance of TLR activation and the regulatory influence of nicotinic cholinergic or ATI receptors will be tested in the mouse model of chronic ang ll-induced hypertension. Anticipated results. The results will establish the importance of innate immune system in triggering the inflammatory cascade that leads to hypertension. The regulatory influence of nicotinic and ATI receptors deflne a new and important putative therapeutic intervention in hypertension and cardiovascular disease. RELEVANCE (See instructions): Relevance. A novel concept deflnes the importance of the.innate immune system in initiating the inflammatory cascade in hypertension. The correlation between the expression of proinflammatory genes and end-organ damage establishes pathological relevance and raises the hopeful prospect of putative therapeutic interventions.